The goals of this research are to develop advanced magnetic resonance spectroscopy (MRS) and imaging techniques and to apply them and other complementary methods to studying brain metabolism, neurotransmission and enzyme activity (protocol no. 11-M-0045, NCT no. 01266577; protocol no. 05-M-0144, NCT no. 00109174). MRS allows measurement of neurotransmission of glutamate and GABA in vivo, which play important roles in many major psychiatric diseases including depression and schizophrenia. During 2012-2013, we have made significant progress in the development and applications of novel spectroscopic and imaging techniques for studying metabolism and neurotransmission in vivo in the brain. From our previous work, we have found that 13C labeling of glutamate and glutamine can be measured from human subjects by low power proton stochastic decoupling in the carboxylic/amide spectral region (Xiang, et al, NMR Biomed, 2011). We further extended this technique to acetate infusion with spectral editing (Xiang et al, J Magn Reson, 2012). Now we are able to distinguish 13C-glutamate C5 from 13C-labeled acetate, by using J coupling difference, although they resonant at the same frequency. Since acetaet is predominantly metabolized in astroglia this will allow us to measure the main metabolic flux from astroglia to neurons while taking advantage of the low decoupling power requirements (Shen, Front. Neuroenergetics, 2013). We are making progress in developing low decoupling power 13C MRS on a whole body 7 Tesla scanner for measuring glutamate in the prefrontal cortex. Preliminary validation of this method has been made on a 3 Tesla scanner (Li et al, J. Magn. Reson., 2012). For proton MRS, after overcoming daunting technical challenges, we have succeeded in obtaining high quality MRS data using the 7 Tesla whole body scanner. We developed our own methods for radio frquency pulse calibration, magnetic field correction, and multichannel data combination (An et al, J. Magn. Reson. Imaging, 2013). From this effort, we have developed 7 Tesla single-shot methods for measuring N-acetylaspartylglutamate (NAAG), glutamate, glutamine and glutathione (An et al, Magn Reson Med, under minor revision). Building on our previous collaborations with Dr. Zarate's group we are now measuring the effect of ketamine on glutamate at 7 Tesla. Collaborations with Dr. Hasler's group have led to understanding the genetic underpinning of amino acid GABA concentration in panic disorder (Preuss et al, Intl J. Neuropsychopharmacology, 2013) as well as age-modulated association between prefrontal NAA and the BDNF gene (Salehi et al, Intl J. Neuropsychopharmacology, 2013). Finally, we discovered a mechanism for restoring the magnetization excitation profile during rapid trasverse relaxation, which, we believe, will facilitate the forthcoming development of the NIH 11.7 Tesla whole body scanner.